INDOLOCARBAZOLE COMPOUND USEFUL AS PROTEINKINASE C INHIBITOR

Abstract: A novel secondary metabolite having formula (I) is isolated from a mutant strain of Streptomyces longisporoflavus. The compound has valuable pharmaceutical properties, e.g., is an inhibitor of proteinkinase C.

Description: INDOLOCARBAZOLE COMPOUND USEFUL AS PROTEINKINASE C INHIBITOR The invention relates to a novel secondary metabolite obtainable from a mutant strain of Streptomvces longisporoflavus having the formula or to a pharmaceutically acceptable salt thereof. As such the compound of the formula (I) is the 3'-demethyl derivative of staurosporine having the formula Based on physicochemical data, e.g. the coupling constants observed in -NMR spectroscopy it is assumed that the absolute configuration of the compound of the formula (I) is the same as in staurosporine. Pharmaceutically acceptable salts of compound (I) or (II) are, for example, salts with suitable mineral acids, such as hydrohalic acids, sulfuric acid or phosphoric acids, e.g., hydrochlorides, hydrobromides, sulfates, hydrogen sulfates or phosphates, salts with suitable aliphatic or aromatic sulfonic acids or N-substituted sulfamic acids, e.g. methanesulfonates, benzenesulfonates, p-toluenesulfonates or N-cyclohexylsulfamates (cyclamates), or salts with strong organic carboxylic acids, such as lower alkanecarboxylic acids or optionally unsaturated or hydroxylated aliphatic dicarboxylic acids, e.g. acetates, oxalates, malonates, maleates, fumarates, malates, tatrates or citronates. The invention further relates to a process for the production of the compound of the formula (I), which process comprises cultivating Streptomvces longisporoflavus mutant strain M14 (DSM 8325) in a suitable nutrient medium and isolating said compound. In particular, the process comprises cultivating Streptomvces longisporoflavus mutant M14 (DSM 8325) in a culture medium containing assimilable sources of carbon, sources of nitrogen and mineral salts, separating the cells from the culture broth and extracting it with an organic water-immiscible solvent, separating the organic phase from the aqueous phase, concentrating the organic phase by evaporation and purifying the resulting crude compound of the formula (I) by means of chromatography and/or crystallization from the same or a different organic water-immiscible solvent. As nutrient medium it is preferred to use an aqueous solution or suspension which contains suitable sources of carbon and nitrogen as well as mineral salts. Particularly suitable sources of carbon and nitrogen are complex organic substances, such as proteins and protein hydrolysates, typically casein, peptone, meat extract, yeast extract, cotton seed, soybean meal, peanut meal, sun-flower seed derived protein nutrient, etc. Suitable mineral salts typically include chlorides, carbonates, sulfates and phosphates of alkali metals and alkaline earth metals, for example sodium, potassium, calcium and magnesium, and also commercially available trace element mixtures. It is also advantageous to add further growth-promoting substances, especially vitamins, conveniently in the form of commercially available standard vitamin solutions. It is preferred to use the nutrient media employed in the Examples herein. Cultivation is carried out aerobically, i.e. conveniently in surface cultures, or preferably submerged with shaking or stirring while introducing air or oxygen into the shaking flask or fermenter. Cultivation is preferably carried out in the neutral pH range, i.e. at about pH 5-8, preferably at pH 6-7, and in the temperature range from about 25-30°C, preferably at about 28°C. The cultivation time is preferably from 3 to 5 days. To isolate the compound of the formula (I) the biomass is separated from the culture broth when cultivation is complete, and extracted with an organic water-immiscible solvent. Suitable organic solvents include esters of aliphatic acids, typically lower alkyl esters, such as methyl or ethyl esters, of lower alkanoic acids such as acetic acid, and halogenated hydrocarbons, e.g. methylene chloride or chloroform. Extraction of the aqueous culture broth can be done twice or three times. After concentrating the combined extracts by evaporation, the residue is further purified by chromatographic means, e.g. by means of column chromatography (such as HPLC or flash chromatography) or TLC. Alternatively or additionally, the product may be crystallized from an organic water-immiscible solvent such as one of those detailed above. The compound of the formula (I) can be conveniently crystallized e.g. from ethyl acetate. The novel compound has valuable, especially pharmacologically valuable, properties and can be used for the prevention and treatment of diseases in a mammal, such as a human or an animal. For example, the compound of the formula (I) is a selective inhibitor of isotypes of the enzyme proteinkinase C. While staurosporine of the formula (II) shows no significant differences in the inhibition of isotypes of the enzyme proteinkinase C, the compound of the formula (I) most selectively and preferentially inhibits isotypes alpha, beta-2 and gamma whilst, e.g., isotypes beta-1 and eta are inhibited to a much lower degree (by a factor of 5-10). Isotypes alpha, beta-2 and gamma of proteinkinase C are inhibited by the compound of the formula (I) already at a concentration (IC 50 ) of approximately 0.04 μmol/liter. The compound of the formula (I) inhibits other enzymes, for example proteinkinase A, protein-phosphorylase-kinase and protein-tyrosin-kinase, only at much higher concentrations. This demonstrates the surprising selectivity of the compound of the formula (I). As can already be expected on the basis of the above-mentioned inhibitory action on isotypes of proteinkinase C, the compound of the formula I has antiproliferative properties which can be demonstrated by the inhibitory action on the growth of human T24 bladder carcinoma cells. Due to the above described properties, the compound of the formula (I) can be used, in particular, for the prophylaxis or treatment of diseases which respond to proteinkinase C inhibition. It can also be used as an antitumor active ingredient, for example for the therapy of tumors of the bladder. The novel compound can be used furthermore for the treatment of multidrug resistant tumors, in particular P-glycoprotein mediated resistance, and shows synergistic effects when combined with other antitumor active compounds, particularly all those showing cross-resistance in MDR (multidrug resistance) like doxorubicin, daunorubicin, vincristine, vinblastine, etoposide, taxol, mitomycin C, actinomycin D or mitoxantrone. Moreover, the compound of the formula (I) is a potent inhibitor of the osteoclast proton pump (OPP). Osteoclasts are a class of bone cells responsible for bone resorption which, during normal bone remodeling, is followed faithfully by osteoblastic bone formation. Osteopenia results from an imbalance of the opposing activities of osteoclasts and osteoblasts such that the rate of bone resorption exceeds the rate of accretion. Osteoclasts resorb bone by secreting protons and lysosomal enzymes into a sealed extracellular lacuna beneath the cell. The resulting low pH demineralizes the bone and activates the secreted lysosomal enzymes which then digest the exposed organic collagen matrix. The protons are pumped out of the osteoclasts by an ATP-dependent H + -pump (H + -ATPase proton pump, osteoclast proton pump) located in the ruffled border membrane of the cell bordering the extracellular lacuna. Inhibition of proton secretion would offer a way to control bone loss. The osteoclast proton pump appears to be a member of the multimeric vacuolar class of H + -ATPase enzymes present in the membrane of a variety of intracellular vacuoles (e.g. clathrin-coated vesicles, chromaffin granules, lysosomes). Surprisingly, and contrary to what is known from staurosporine and its derivatives, the compound according to the invention is an extremely potent inhibitor of H + - ATPase proton pump isolated from clathrin-coated vesicles from bovine brain. The inhibitory concentration (IC 50 ) is approximately 0.0006 μM. Due to the inhibitory action on H + - ATPase proton pumps the compound according to the invention can be used for the prevention or treatment of the elevated bone loss characteristic of a variety of pathological conditions such as primary osteoporosis (juvenile, idiopathic, congenital, postmenopausal, involutional) and secondary osteopenia associated with maUgnancy, renal insufficiency, endocrinopathies, malabsorption syndromes, hepatic disease, immobilization, arthropathies and iatrogenic causes. Another field of application is enhancing the function of cholinergic neurons, striatal neurons, and sensory neurons, e.g., dorsal root ganglion neuron. Furthermore, the inventive compound can be used in a method for protecting nerve cells of mammal from degeneration induced by excitatory amino acids. Examples are Alzheimer's disease, moto neuron disease, Parkinson's disease, cerebrovascular disease, AIDS dementia, epilepsy, Huntington's disease and concussive or penetrating injuries to the brain or spinal cord. In these cases the inventive compound can be administered in combination with a neurotrophic factor, preferably a member of the neurotrophic family, and most preferably nerve growth factor (NGF). The invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of the active ingredient, in particular an amount which is effective for the prophylaxis or therapy of one of the above-mentioned diseases, together with pharmaceutically acceptable carriers which are suitable for topical, for example in the treatment of skin tumors, enteral, for example oral or rectal, or parenteral (for example i.v., s.c. or transdermal) administration, and which can be inorganic or organic, solid or liquid. Compositions which are used for oral administration are, in particular, tablets or gelatine capsules which comprise the active ingredient together with diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycerol, and/or lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol. Tablets can also comprise binders, for example magnesium aluminum silicate, starches such as maize, wheat or rice starch, gelatine, methylcellulose, sodium carboxylmethylcellulose and/or polyvinylpyrrolidone and, if desired, disintegrants, for example starches, agar, algic acid or a salt thereof such as sodium alginate, and/or effervescent mixtures, or adsorbants, colorants, flavourings and sweeteners. The pharmacologically active compound of the present invention can furthermore be used in the form of compositions which can be administered parenterally, or solutions for infusion. Such solutions are preferably isotonic aqueous solutions or suspensions, it being possible for those to be prepared prior to use, for example in the case of lyophilized compositions which comprise the pure active ingredient or the active ingredient together with a carrier, for example mannitol. The pharmaceutical compositions can be sterilized and/or comprise excipients, for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating the osmotic pressure and/or buffers. The present pharmaceutical compositions which, if desired, can comprise further pharmacologically active substances, are prepared in a manner known per se, for example by means of conventional mixing, granulating, sugar-coating, dissolving or lyophilization processes and comprise from approximately 0.01 % to 90 %, in the case of lyophilizates up to 100 %, in particular from approximately 0.1 % to approximately 50 %, of the active ingredient, a concentration of active ingredient of below 1 % being particularly suitable for compositions for topical administration. The invention also relates to the use of the compound of the formula I, preferably in the form of pharmaceutical compositions, for the prophylaxis or the therapeutic treatment of the human or animal body, in particular in the case of the above-mentioned diseases. The invention especially relates to a method for inhibiting proteinkinase C, especially the above-mentioned isotypes thereof, in a warm-blooded species requiring such a treatment, whereby an effective proteinkinase C-inhibiting dose of the compound of the formula I is administered to this representative of a warm-blooded species. The invention likewise especially relates to a method for inhibiting osteoclast proton pump in a warm-blooded species requiring such a treatment, whereby an effective osteoclast proton pump-inhibiting dose of the compound of the formula I is administered to such warm-blooded species. The dose of the active ingredient depends, inter alia, on the type and severity of the disease, the nature and size of the species to be treated, the age and condition of the species, the response to treatment and the way in which the active ingredient is administered. For example, a representative of a warm-blooded species having a body weight of approximately 70 kg is administered a daily dose of 1 mg to 1500 mg, preferably 10 mg to 500 mg, of the compound of the formula I. This total daily dose is preferably split into 1-3 daily administrations. The dose in the case of oral administration is approximately two to three times higher than in the case of parenteral administration, i.e. rather in the upper range of the above-mentioned doses. The novel compound of the formula (I) is furthermore a valuable intermediate for the production of other pharmaceutically active compounds such as compounds inhibiting subtypes of proteinkinase C or osteoclast proton pump. The novel strain Streptomvces longisporoflavus M14 DSM 8325 is a further embodiment of the present invention. The examples which follow illustrate the invention without any restriction whatsoever. Experimental part 1. Production and isolation of Streptomvces longisporoflavus mutant M 14 Three Petri dish cultures of Streptomvces longisporoflavus strain R19/col.l5 (isolated from soil) were prepared and were left incubated at 28°C for 5-7 days on sporulation agar SPA: soluble starch (maize starch) 20 g/1 yeast extract 4 g/1 agar 20 g/1 pH before sterilization: about 7 The cultures exhibited a white to grey color on the surface of the mycelium. After incubation, a sterile Tween 80 solution (0.5%) was added to each plate. Spores were removed by scraping the surface of these plates with an inoculating loop by gentle pressure. The spore suspension obtained was then transferred to a glass Petri dish. The spore concentration is controlled and determined with a microscope. The suspension was irradiated under the UV lamp with constant agitation: 500m W/cm 2 during 50". The irradiated spore suspension was then diluted by factor 100 to 1000, left for 1 day at room temperature in the dark, and then plated out on complete medium plates (sporulation agar SPA). The plates were left incubated at 28°C in the dark for 5 days and then they were replica-plated to "minimal medium" (MM) 1-asparagine 0.5g/l K 2 HPO 4 -3H 2 O 0.65 g/1 MgSO 4 -7H 2 O 0.2 g/1 FeSO 4 -7H 2 O 0.01 g/1 glucose 10.0 g/1 pH 7.0-7.2, minimal medium completed with tryptophan (MMT) and complete medium (SPA). After 4 days of incubation at 28°C, the replicas were compared to the originals. The colonies which were different with regard to shape, color, size and development on minimal medium were isolated from the plates, fermented and the culture broths were analyzed by TLC and HPLC. One colony appeared to have a poor and thin development on both minimal media but a normal development on the complete medium (so-called ghost colony) and was designated mutant M 14. The TLC and HPLC analysis of the culture broth extracts of the mutant M14 after 5 days of fermentation in medium NL3 mannitol 40 g/1 Sunpro (Pharma media) 20 g/1 KH 2 PO 4 0.5 g/1 SAG 471 0.5 g/1 pH before sterilization: 6.5 pH after sterilization: 6.31 showed that M14 produces mainly one compound: On TLC: (CH 2 Cl 2 /isopropanol 10:1) Rf compound (0.69)< Rf staurosporine (°- 14 )' (extraction : culture broth/CH2θ2 1:1). In HPLC: R t compound (~ 8 min >< R t staurosporine (~ 9 - 5 min )> (extraction : culture broth / methanol 1:1, centrifugation). HPLC conditions: UV detector (Spectra Physics): 290nm, Pump (Spectra Physics), Column: LiChrospher 100 RP-8; 5μm; 4x125 mm (cartridge); solution A: phosphate buffer pH=3 degassed with helium, solution B: acetonitrile/solution A 80:20 degassed with helium; minimal pressure: 20 bar, maximal pressure: 300 bar, normal pressure during the analysis: 60-70 bar; flow: 1.25 ml/mn; injection volume: 20 ml. Gradient conditions: Time (min) Solution A Solution I 0 60 40 16 0 100 17 0 100 19 60 40 23 60 40 Further description of the mutant strain Streptomvces longisporoflavus M14: - mycelium yellow to brown on sporulation agar SPA, - development similar as the original strain Streptomvces longisporoflavus R19/coll5, - small white pellets of up to 3mm diameter in liquid medium NL 148a, - productivity: about 150 mg of 3'-demethyl staurosporine in medium NL3 after 4 days of culture. 2. Fermentation of Streptomvces longisporoflavus mutant M 14 on a 30 1 scale The fermentation is started using 2 inoculum stages. Media used for the preculture and fermentation are the following ones: preculture medium NL 148a mannitol 22 g/1 Lab lemco (Oxoid) 4 g/l peptone C 5 g/1 yeast extract 0.5 g/1 Casitone (Bacto) 3 g 1 NaCl 1.5 g/1 pH before sterilization: 7.6 pH after sterilization: 6.5 - 6.8; fermentation medium NL 3 (antifoam SAG 471 is added only if necessary), see above. The temperature used is about 28°C. The inoculum stages are performed at a pH from about 7.6, whereas the fermentation is performed at a pH from about 6.0 to 7.0. a. First Preculture Cryo-tubes, slants or agar plates are used to inoculate Erlenmeyer flasks containing the medium NL148a. The flask is left to incubate at 28°C for 48 hours at 220 rpm. One milliliter of fresh culture is used to inoculate 100 ml of medium NL 148a in 500 ml Erlenmeyer flasks with 1 baffle (1% inoculum). The flasks are left to incubate at 28°C for 48 hours at 250 rpm. b. Second Preculture Twenty-five milliliters from the first preculture are used to inoculate 500 ml of medium NL 148a in 2000 ml Erlenmeyer flasks with 4 baffles (5% inoculum). The flasks are left to incubate at 28°C for 48 hours at 120 rpm. c. Production stage (Fermentation) Six hundred milliliters of the second preculture are used to inoculate 30 1 of the fermen¬ tation medium NL 3 (2% inoculum). The fermentation is performed for 117 hours at 28°C with agitation and aeration at 600 rpm, lv/v/min. and 0.5 bar over pressure. No pH adjustment is made during the fermentation. The rpm is controlled in such a way that O 2 saturation does not fall below 30%. Metabolite production is followed by HPLC analysis. 3. Isolation of 3'-demethyl staurosporine a. from shake flask cultures About 1.5 liter of the culture broth of a shake flask culture obtained in accordance with Example 2 is intensively stirred with 21 of CH2CI2. The extracted cell material is removed by filtration using Hyflo (diatomaceous earth used as a filter aid) and the two phases are separated. The aqueous phase of the clear filtrate is submitted to an additional extraction step using 2 1 of ethyl acetate. The combined organic extracts are dried over anhydrous sodium sulfate and evaporated to dryness. After crystallization from a small volume of ethyl acetate 3'-demethyl staurosporine is obtained as a pale yellow crystallizate. Melting point > 220°C (under decomposition). Optical rotation α (dioxane, c= 1% w/v, 20°C): +26.1° (at 436 nm), +13.2°±5.3° (at 546 nm), +11.1°±5.3 0 (at 578 nm), +11.1°±5.3° (at 589 nm, sodium D 2 line). FAB-MS (instrument ZAB HF, positive mode with thioglycine): 453 (M-H + ); further major signals at (m/e) 338, 311, 295 and 142. Exact molecular weight: 452.517 (C27H24N4O3) UV (95% ethanol, 10^M): 6, 293, 240 and 205 nm. l H NMR in DMSO-d 6 (at 80°C): 9.30 (d, IH, H-4), 8.27 (s, IH, H-6), 8.02 (d, IH, H-8), 7.98 (d, IH, H-ll), 7.61 (d, IH, H-l), 7.50 (dd, IH, H-2), 7.46 (dd, IH, H-10), 7.35 (t, IH, H-3), 7.29 (t, IH, H-9), 6.92 (dd, IH, H-6'), 6.12 (br., OH), 4.99 (d, IH, H-7), 4.94 (d, IH, H-7'), 4.84 (dd, IH, H-3'), 3.77 (ddd, IH, H-4'), 3.02-2.95 (m, IH, H-5'a), 2.62 (s, 3H, 4'-CH 3 -NH), 2.31 (s, IH, 2'-CH 3 ), 2.26 (ddd, IH, H-5'b). Coupling constants (Hz): J 2 = 3 . = 8.0; J 8 . 9 = Jιo.n = 8-0; l 3 '. 4 ' =3.2', Jy j»= 1.2; J 4' ^ 'a = 4.0; J4-^ 'b =: 12.4; Js 't ^ 5 ' b = 12.5; 5' .6 ,= 8- ; J5'b. 6 ,= 6.2. 13 C NMR in DMSO-d 6 (at 80°C): 171.5; 138.8; 136.0; 132.3; 129.3; 125.4; 125.1; 124.8; 124.3; 123.9; 122.5; 120.7; 119.8; 119.0; 114.9; 113.9; 113.8; 108.2; 94.3; 80.5; 68.4; 53.7; 45.1; 30.1; 28.5; 25.8. IR (KBr): 3420, 3252, 3049, 2930, 1660, 1587, 1458, 1420, 1398, 1348, 1317, 1283, 1250, 1227, 1173, 1151, 1126, 1101, 1070, 1045, 1020, 955, 922, 851, 822, 789, 773, 744, 663, 631 cm "1 (the most prominent absorption bands are underlined). The spectroscopic data are in full accordance with the depicted structure. b. from A-fermenter cultures The fermentation broths obtained from different fermenter cultures (see example 2c) are combined to yield 77 1. After addition of 10 kg of Hyflo the whole broth is extracted by vigorous stirring with twice the volume of ethyl acetate. After filtration the filter cake is washed with an additional volume of 301 of ethyl acetate. The combined organic phases are separated, concentrated and evaporated to dryness. The crude extract is triturated with 11 of n-heptane. The evaporation of the heptane phase gives a residue of a thin oil, which according to TLC analysis is completely devoid of staurosporine related compounds. The heptane-insoluble residue is dissolved in dichloromethane which leads to a spontaneous crystallization of a first crop of crystals. The raw crystallizate is dissolved in methanol, treated with active carbon and filtered. The clear filtrate is concentrated and recrystallized from ethyl acetate. The mother liquor and the previously obtained solution in dichloromethane are combined and chromatographed on a 1 1 column with silicagel Si 60 (Merck, particle size 15-25 μm). The fractions containing the desired product are eluted with a solvent mixture consisting of 95 % dichloromethane and 5 % methanol, combined and evaporated to dryness. Rechromatography of these fractions using the same method leads to semipure material. Recrystallization from ethyl acetate yields a second crop of pure substance. The mother liquors are further purified by a repeated chromatography and recrystallization cycle which produces a third crop of pure substance. Crystallizates and chromatographic fractions containing the desired product are pooled and crystallized from ethyl acetate. The pale yellow crystals are isolated by filtration and dried under high vacuum. The physico-chemical properties of the product are identical to those of the product obtained in example 3a. 4. Pharmaceutical composition Tablets comprising 50 mg of active ingredient are prepared in the customary manner in the following composition: Composition: Active ingredient 50 g Wheat starch 150 g Lactose 125 g Colloidal silica 10 g Talc 20 g Magnesium stearate 2 g 357 g Preparation: The active ingredient is mixed with some of the wheat starch, the lactose and colloidal silica, and the mixture is passed through a sieve. Some more wheat starch is made into a paste with 5 times the amount of water in a water bath, and the powder mixture is kneaded with this paste until a slightly kneadable composition has been formed. The kneadable composition is pressed through a sieve of mesh size approx. 3 mm and dried, and the dry granules obtained are passed again through a sieve. The remainder of the wheat starch, the talc and the magnesium stearate are thereinafter admixed, and the mixture is compressed to give 1000 notched tablets of 357 mg weight each containing 50 mg of active ingredient. 5. Preparation of 3'-demethyl staurosporine methanesulfonate salt A solution of 0.65 ml (10 mmol) of methanesulfonic acid in 10 ml of deionized water is added under stirring to a suspension of 5.12 g (10 mmol) 3'demethyl staurosporine (as obtained in example 3b) in 250 ml of deionized water. The addition is completed within 30 minutes. Stirring is continued during additional 45 min. until the suspension is almost completely dissolved. The remaining solid particles are removed by filtration. The clear filtrate is lyophilized. The residue is dissolved in methanol and treated with activated charcoal. The filtered solution is concentrated until crystallization occurs. The resulting precipitate is filtered and dried under high vacuum. According to the elemental analysis the purified material contains 2.5 molar equivalents of water and decomposes at a temperature above 200°C. Deposition of microorganism: The strain Streptomvces longisporoflavus M14 was deposited on May 27, 1993 with the Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSM) (German Collection of Microorganisms and Cell Cultures) in Braunschweig, FRG, under No. DSM 8325.

Claims: Claims 1. A compound of the formula or a pharmaceutically acceptable salt thereof. 2. A compound of the formula according to claim 1 exhibiting the following chemical shifts and coupling constants J (Hz) in *H NMR (DMSO-d 6 , 80°C): - 9.30 (d, IH, H-4), 8.27 (s, IH, H-6), 8.02 (d, IH, H-8), 7.98 (d, IH, H-ll), 7.61 (d, IH, H-l), 7.50 (dd, IH, H-2), 7.46 (dd, IH, H-10), 7.35 (t, IH, H-3), 7.29 (t, IH, H-9), 6.92 (dd, IH, H-6'), 6.12 (br., OH), 4.99 (d, IH, H-7), 4.94 (d, IH, H-7'), 4.84 (dd, IH, H-3'), 3.77 (ddd, IH, H-4'), 3.02-2.95 (m, IH, H-5'a), 2.62 (s, 3H, 4'-CU 3 -NH), 2.31 (s, IH, 2'-CH 3 ), 2.26 (ddd, IH, H-5'b); 12.4; J5 > a .5'b- 3. A pharmaceutical composition comprising a compound of the formula (I) according to claim 1. 4. A compound of the formula (I) for use in the prophylactic or therapeutic treatment of the human or animal body. 5. A process for the production of a compound of the formula (I) according to claim 1, comprising cultivating Streptomvces longisporoflavus mutant M14 (DSM 8325) in a suitable nutrient medium and isolating said compound. 6. A compound obtainable by the process according to claim 5 or a pharmaceutically acceptable salt thereof. 7; The strain Streptomvces longisporoflavus M14 (DSM 8325).

Inventors: GHISALBA ORESTE, HOEHN-THIERRY PASCALE, MOERKER THEOPHILE, PETER HEINRICH, GHISALBA, ORESTE, HOEHN-THIERRY, PASCALE, MOERKER, THEOPHILE, PETER, HEINRICH
Applicants: CIBA GEIGY AG, GHISALBA ORESTE, HOEHN THIERRY PASCALE, MOERKER THEOPHILE, PETER HEINRICH, CIBA-GEIGY AG, GHISALBA, ORESTE, HOEHN-THIERRY, PASCALE, MOERKER, THEOPHILE, PETER, HEINRICH
Application year: 1994
Main classification: C07D498
IPC codes: A61K31, A61P43, C07D498, C12P17, C12R1